In December 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was first reported in Wuhan, China. Shortly afterwards, SARS-CoV-2 infected hundreds of millions of people around the world and has claimed more than 4.69 million lives to date. This ongoing pandemic is commonly referred to as the 2019 Coronavirus Disease (COVID-19) Pandemic.
Scientists have sequenced SARS-CoV-2 and found a high similarity between this virus and SARS-CoV. Both coronaviruses infect humans by binding to angiotensin converting enzyme 2 (ACE2) receptors that are present on the cell surface.
Previous studies have described the molecular interactions between the receptor binding domain (RBD) of SARS-CoV-2 and the host’s ACE2 receptor during the course of infection. These studies helped develop potential therapeutic strategies, such as blocking the spike-ACE2 interaction to prevent SARS-CoV-2 infection.
Study: Development of a novel, pan-variant aerosol intervention for COVID-19. Image Source: Crystal Eye Studio / Shutterstock.com
Therapeutic strategies to contain COVID-19
Scientists have identified several peptides and proteins with high binding affinity that have therapeutic potential in the treatment of COVID-19. In addition, they have successfully developed antibodies that can block the spike-ACE2 interaction.
Several of these antibodies have received emergency approval (EUA) from various regulatory agencies, such as the U.S. Food and Drug Administration (FDA), to be used independently or in combination to treat COVID-19.
Researchers have also recommended the use of recombinant ACE2 as a robust therapeutic option. This is because, as mentioned above, the entry point of the original SARS-CoV-2 strain, as well as its variants, is the host’s ACE2 receptor. Although several studies have indicated multiple entry receptors, ACE2 remains the main SARS-CoV-2 receptor in vivo.
In 2003, after the SARS-CoV outbreak, scientists developed soluble recombinant human ACE2 (APN01) for the systemic treatment of acute respiratory distress syndrome (ARDS). This therapeutic intervention reduces the damage in the lungs caused by SARS-CoV through the catalytic activity of ACE2 in cleaving Ang II. Both phase I and phase II clinical studies have shown that APN01 is safe and highly capable is to reduce pathogenic Ang-II levels.
Effectiveness of APN01 against COVID-19
Scientists have since conducted in vitro studies to analyze the SARS-CoV-2 neutralizing activity of APN01 in human organoids and cells. Studies of the interactions between the spike (S) proteins of SARS-CoV-2 variants of concern (VoC) and variants of interest (VoI).
To this end, these studies have shown that APN01 offers significantly higher affinity. It is important that APN01 neutralizes all tested SARS-CoV-2 VoCs and VoIs.
Recently, APN01 underwent a phase II randomized clinical trial for the treatment of severe SARS-CoV-2 infection by intravenous administration. However, scientists have indicated that one of the difficulties in tackling the current pandemic is the intravenous nature of therapeutic interventions. This is because treatment requires qualified healthcare professionals, which can be difficult due to a lack of staff or facilities.
About the study
Researchers hypothesized that if APN01 could be introduced directly into an infected person’s airways, it could locally neutralize SARS-CoV-2. This would prevent the virus from spreading further into the lungs, which would then be protected from virus damage through the deregulated signal transmission in the renin angiotensin (RAS) and kinin signaling pathways. This study is available on the bioRxiv * preprint server.
The authors of this study tested their theory in a SARS-CoV-2 mouse model. In this experiment, infected mice were subjected to clinical grade APN01 treatment.
The mice that received the treatment showed less weight loss and did not die from the infection. Therefore, scientists reported a strong protective effect with this experimental treatment method.
The primary strategy for this new route of drug delivery was the aerosol formulation of APN01. The researchers ensured that after the aerosolization of APN01, the virus-binding activity as well as the enzymatic activity to cleave Ang II was maintained.
The authors of this study succeeded in developing a safe inhalable APN01. They conducted experiments to optimize the effective dosage. For the toxicological evaluations, they carried out tests on dogs by administering them to an aerosol twice a day for two weeks at the maximum possible concentration. However, no significant toxicities were found.
Following these reports, a Phase I clinical trial in healthy volunteers will be initiated shortly. Then the Phase II study would begin, in which people with COVID-19 will participate. Scientists are optimistic that this new strategy could serve as a rapidly actionable therapy to treat COVID-19 against the original strain as well as against VoCs and VoIs.
One of the limitations of this study is the use of a single species in toxicology experiments. Taken together, this research provides evidence of how an inhalable therapeutic might be effective against the current and future SARS-CoV-2 variants.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore are not considered conclusive, guide clinical practice / health-related behavior, or should be treated as established information.